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41467 2018 4362 Moesm1 E Supplementary Information Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function Davies et al. 1 Supplementary Notes Supplementary Note 1 Phenotype Descriptions UK Biobank Verbal-numerical reasoning test. At baseline, a sub-sample of UK Biobank participants were administered the verbal-numerical reasoning test (n = 187,211; referred to as the ‘fluid intelligence test’ by UK Biobank). Participants were asked 13 multiple-choice questions that assessed verbal and numerical problem solving. The score was the number of questions answered correctly in two minutes. This test has been shown to have adequate test- retest reliability (r = 0.65)1 and internal consistency (Cronbach α = 0.62)2. The verbal- numerical reasoning test was also administered to three sub-samples of participants at, the first repeat assessment visit (n = 20,115), the imaging visit (n = 15,750) or during a web- based cognitive assessment (n = 123,665). In the web-based version of this test there was an additional question, thus the maximum score was 14. Four samples of UK Biobank participants with verbal-numerical reasoning scores were used in the current analysis. The first sample (VNR Assessment Centre) consists of UK Biobank participants with genome-wide genotyping data, following quality control procedures, who also completed the verbal-numerical reasoning test at baseline (n = 107,586). The second sample (VNR T2) consists of participants who did not complete the verbal-numerical reasoning test at baseline but did complete this test at the first repeat assessment visit in assessment centres (n = 11,123). The third sample (VNR MRI) consists of participants who did not complete the verbal-numerical reasoning test at a previous testing occasion but did complete the test at the imaging visit in assessment centres (n = 3002). The fourth sample (VNR Web-Based) consists of UK Biobank participants with genome-wide 2 genotyping data who did not complete the verbal-numerical reasoning test at any assessment centre visit but did complete this test during the web-based cognitive assessment (n = 46,322). In this analysis, samples were analysed separately because there were differences in both the test questions and the testing environment. Reaction time test. At the baseline UK Biobank assessment, 496,790 participants completed the reaction time test. Here, participants were presented with pairs of cards on the computer screen. The two cards could either be the same or different. If the two cards were identical, participants were to push a button box as quickly as possible. There were 12 trials in total. The first five were used as a practice. Of the remaining seven trials, four presented matching cards. The score is the mean time, in milliseconds, to correctly identify the matching cards in these four trials. While there are only a few trials, internal consistency is good (Cronbach α = 0.85)2. For the current analysis, a sample of 330,069 UK Biobank participants with both scores on the reaction time test and genotyping data were used. CHARGE Cohorts 3C-Dijon. Scores on the following cognitive ability tests were used to create the fluid-type general cognitive function component: Trail Making Test B (TMTB; time to complete part B – in seconds), Benton Visual Retention Test (BVRT; number of questions answered correctly), and Delayed Recall (Five Words Memory Test; number of words correctly remembered). The tests, the method of application and key references have been described in detail elsewhere3. The listwise N was 3,652. The Pearson correlations (rs) among the 3 tests ranged from -0.34 to 0.14 (mean of absolute values = 0.20). Principal components analysis was applied to these 3 tests. The first unrotated principal component (FUPC) accounted for 47.4% of the total test variance. Loadings on the FUPC were as follows: Delayed Recall = 0.49, BVRT = 0.77 and TMTB = -0.76 3 AgeCoDe. Scores on the following cognitive ability tests were used to create the fluid-type general cognitive function component: CERAD verbal fluency (number of animals named in one minute), CERAD immediate recall (sum of correctly remembered words over 3 trials; Range: 0-30), CERAD constructional praxis recall (four drawings previously copied should be reproduced from memory; range of performance ratings: 0-11). The tests, the method of application and key references have been described in detail elsewhere4. The listwise N was 617. The rs among the 3 tests ranged from 0.25 to 0.36 (mean of absolute values = 0.29). Principal component analysis was applied to these 3 tests. The FUPC accounted for 52.7% of the total test variance. Loadings on the FUPC were as follows: CERAD verbal fluency = 0.76, CERAD immediate recall = 0.76, CERAD constructional praxis recall = 0.66. AGES. Scores on the following cognitive ability tests were used to create the fluid- type general cognitive function component: Digit Backward Test5 (number of digit sequences remembered backwards), The Digit Symbol Substitution Test5 (DSST; number of correct digit symbol matches made), California Verbal Learning Test6 (CVLT), The Figure Comparison Test7, The Modified Stroop Test8 (Part III – word-colour interference), The Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory9. The tests, the method of application and key references have also been described in detail elsewhere10. Absolute value of the rs among the 6 tests ranged from 0.21 to 0.77 (mean 0.39). Principal components analysis was applied to these 6 tests. The FUPC accounted for 50.1% of the total test variance. Loadings on the FUPC were as follows: Digits backward test = 0.64, DSST total correct cells = 0.87, CVLT 1-4 number of unique target words = 0.73, Figure Comparison total correct in 60 sec = 0.83, STROOP Part III time in sec = -0.62, CANTAB Spatial Working Memory total errors = -0.52. 4 Airwave. Scores on the following cognitive ability tests were used to create the fluid- type general cognitive function component: Reaction (Two-choice reaction time: time taken to select between a left or right response to match a left or right stimulus) , Pairing (Paired associate learning – episodic memory: requires the user to recall the positions of 7 hidden pictures), Quiz (Fluid intelligence: reasoning quiz presents multiple-choice questions, alternating between numerical and verbal problems), Stroop (Mild interference/Stroop interference; This test measured the effect on two-choice reaction time of increasing choice complexity), Number (Working Memory Test - Forward digit span). The listwise N was 9,908. Principal component analysis was applied to these 5 tests. The FUPC accounted for 33.2% of the total test variance. Loadings on the FUPC were as follows: Reaction = 0.61, Pairing = 0.45, Quiz = -0.58 Stroop = 0.70, Number = -0.50. ARIC. Scores on the following cognitive ability tests were used to create the fluid- type general cognitive function component: Delayed Word Recall Test (total number of words recalled), Digit Symbol Substitution Test (total number of correct symbols), Word Fluency Test (sum of words produced beginning with the letters F, A, and S). The tests, the method of application and key references have been described in detail elsewhere11-13. The listwise N was 10,534. The rs among the 3 tests ranged from 0.24 to 0.43 (mean 0.34). Principal components analysis was applied to these 3 tests. The FUPC accounted for 56.1% of the total test variance. Loadings on the FUPC were as follows: Delayed Word Recall Test = 0.52, Digit Symbol Substitution Test = 0.63, Word Fluency Test = 0.58. ASPS. Scores on the following cognitive ability tests were used to create the fluid- type general cognitive ability factor: Alterskonzentrations-Test (AKT; concentration test – time in s), Lern- und Gedächtnistest (LGT) (figural memory, total number of correct answers of two figural subtests), Lern- und Gedächtnistest (LGT) (verbal memory, total number of correct answers of three verbal subtests), Complex reaction time task (computerized task; 5 reaction time in ms), Digit Span – backward (length of highest correctly repeated digit list), Purdue Pegboard Test (visuo-practical skills; total number of correct elements in most difficult condition [assembly]), Trail Making Test – Version B (time in s). The tests, the method of application and key references have been described in detail elsewhere14-19. The listwise N was 748. The absolute rs among the 7 tests ranged from 0.125 to 0.528 (mean 0.327). Principal components analysis was applied to these 7 tests. The FUPC accounted for 42.6% of the total test variance. Loadings on the FUPC were as follows: Alterskonzentrations-Test = 0.534, figural memory (LGT) = 0.642, verbal memory (LGT) = 0.725, Complex reaction time task = 0.534, Digit Span = 0.595, Purdue Pegboard Test = 0.722, Trail Making Test-B = 0.774. ASPS-Fam. Scores on the following cognitive ability tests were used to create the fluid-type general cognitive ability factor: Lern- und Gedächtnistest (LGT) (figural memory, total number of correct answers of two figural subtests) 1, Lern- und Gedächtnistest (LGT) (verbal memory, total number of correct answers of three verbal subtests) 2, Complex reaction time task (computerized task; reaction time in ms) 3, Digit Span – backward (length of highest correctly repeated digit list) 4, Purdue Pegboard Test (visuo-practical skills; total number of correct elements in most difficult condition [assembly]) 5, Trail Making Test – Version B (time in s) 6. The tests, the method of application and key references have been described in detail elsewhere15-19. The listwise N was 311. The absolute rs among the 6 tests ranged from 0.217 to 0.619 (mean 0.435). Principal components analysis was applied to these 6 tests. The FUPC accounted for 53.2% of the total test variance. Loadings on the FUPC were as follows: figural memory (LGT) 1 = 0.789, verbal memory (LGT) 2 = 0.809, Complex reaction time task 3 = 0.560, Digit Span 4 = 0.606, Purdue Pegboard Test 5 = 0.783, Trail Making Test-B 6 = 0.786.
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